Abstract
The purpose of this study was to investigate the effects of three weeks of rosuvastatin (Ros) treatment alone and in combination with voluntary training (Tr) on expression of genes involved in cholesterol metabolism (LDLR, PCSK9, LRP-1, SREBP-2, IDOL, ACAT-2 and HMGCR) in the liver of eight week-old ovariectomized (Ovx) rats. Sprague Dawley rats were Ovx or sham-operated (Sham) and kept sedentary for 8 weeks under a standard diet. Thereafter, rats were transferred for three weeks in running wheel cages for Tr or kept sedentary (Sed) with or without Ros treatment (5mg/kg/day). Six groups were formed: Sham-Sed treated with saline (Sal) or Ros (Sham-Sed-Sal; Sham-Sed-Ros), Ovx-Sed treated with Sal or Ros (Ovx-Sed-Sal; Ovx-Sed-Ros), Ovx trained treated with Sal or Ros (Ovx-Tr-Sal; Ovx-Tr-Ros). Ovx-Sed-Sal rats depicted higher (P < 0.05) body weight, plasma total cholesterol (TC) and LDL-C, and liver TC content compared to Sham-Sed-Sal rats. In contrast, mRNA levels of liver PCSK9, LDLR, LRP-1 as well as plasma PCSK9 concentrations and protein levels of LRP-1 were reduced (P < 0.01) in Ovx-Sed-Sal compared to Sham-Sed-Sal rats. However, protein levels of LDLR increased (P < 0.05) in Ovx-Sed-Sal compared to Sham-Sed-Sal rats. Treatment of Ovx rats with Ros increased (P < 0.05) mRNA and protein levels of LRP-1 and PCSK9 but not mRNA levels of LDLR, while its protein abundance was reduced at the level of Sham rats. As a result, plasma LDL-C was not reduced. Exercise alone did not affect the expression of any of these markers in Ovx rats. Overall, Ros treatment corrected Ovx-induced decrease in gene expression of markers of cholesterol metabolism in liver of Ovx rats, but without reducing plasma LDL-C concentrations. Increased plasma PCSK9 levels could be responsible for the reduction of liver LDLR protein abundance and the absence of reduction of plasma LDL-C after Ros treatment.
Highlights
Incidence of cardiovascular diseases increases with age in women, with a noticeable increase after menopause [1]
We previously reported that high plasma levels of low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) in Ovx rats were accompanied by a reduction of hepatic LDLR, PCSK9, SREBP-2 and LRP-1 (LDL receptor related protein-1) mRNA levels [5]
Ovariectomy led to significant (p 0.05) increases in plasma TC, LDL-C and liver TC levels compared to Sham-SedSal rats
Summary
Incidence of cardiovascular diseases increases with age in women, with a noticeable increase after menopause [1]. Menopause as well as ovariectomy (Ovx) in animals is associated with higher plasma levels of low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) [2,3,4]. We previously reported that high plasma levels of LDL-C and TC in Ovx rats were accompanied by a reduction of hepatic LDLR (low-density lipoprotein receptor), PCSK9 (proprotein convertase subtilisin/kexin type 9), SREBP-2 (sterol regulatory element binding protein 2) and LRP-1 (LDL receptor related protein-1) mRNA levels [5]. The importance of estrogens levels in regulating the PCSK9-LDLR axis has been recently highlighted [6] This is an important consideration since all of these proteins are involved in circulating cholesterol uptake by the liver and constitute primary determinants of plasma LDL-C levels [7]. The ensuing decrease in liver cholesterol levels leads to the activation of SREBP-2 and up-regulation of hepatic LDLR causing increased clearance of plasma LDL-C [9, 10]
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